In our past studies we uncovered several lupus susceptibility genes that, either by themselves or by interacting with a variety of other genetic factors, modify both the induction and progression of autoimmune disease. We previously determined that mice deficient in the IgG receptor FcgammaRIIB develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-deficient mouse model allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to agravate autoimmune disease. We showed, using transgenic overexpression of TLR7, that TLR7 is essential to regulate autoimmunity and dendritic cell homeostasis. These mice provide a prime example of how important it is to control the expression of innate receptors. These studies provide a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. In our analysis of our various murine models of lupus, we detected increased frequency of an uncommon subset identified as NK1.1+CD11c+CD122+MHC-II+. These cells share characteristics with the NK cell lineage and with cells previously described as IKDCs: (1) they depend on IL15 and express E4BP4 (2) they are cytotoxic and produce type I and type II interferon upon activation; (3) they are efficient antigen presenting cells both through MHC-II expression and in cross-presentation to CD8s. We showed that these atypical NK cells were responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They were highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persisted in high numbers for months and maintained their surface marker profile, indicating that this population was developmentally stable. Gene expression analyses on both mRNA and microRNAs showed a modified cell cycle program in which various miR15/16 family members were upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. On the other hand, low expression of miR150, miR181 and miR744 in these cells implied a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells. Characterization of these cells was published in the Journal of Immunology (Voynova et al. 2015) Additionally, we showed that atypical NKs purified from spleens of SLE-prone mice, and identified as NK1.1+CD11c+CD122+MHC-II+, induced persistent autoimmune disease in an IFN-I and CD40L-dependent manner when transferred to WT mice. A single transfer of 4x106 NK1.1+ cells from TLR7tg into WT induces a 2-week-long wave of inflammatory cytokines in the serum, a sustained increase in T cell activation and follicular helper cells for the following months, and a progressive expansion of dendritic cells, monocytes and granulocytes. Furthermore IL15 deficiency, which impedes development of NK cells, ameliorated the autoimmune pathology of TLR7tg mice. These results suggested that cells of the NK lineage can develop into cytokine producing/antigen-presenting cells that affect the priming and progression of systemic autoimmune disease. Experiments showing the induction of disease by transfer of atypical NK cells were reported in a Cutting Edge publication by The Journal of Immunology (Voynova et al, 2015). We expect that these studies will help dissect the requirements for autoimmune pathology and will address the effect of pathogen infections in overall incidence of autoimmune disease. Newly discovered cell populations will possibly uncover potential markers of disease and suggest new routes for modifying ongoing disease in lupus or other autoimmune diseases. In addition, we collaborated with the Su group at LMVR, NIAID to uncover new type-I interferon related pathways that are induced in infection with certain strains of the Plasmodium parasite. Our group performed a methodical testing of signaling potential using a list of genes generated from a cross-species (Mouse/Plasmodium) genetic screen array. Novel interferon-related pathways were uncovered that are now under investigation. This research was published in the journal Cell Reports in 2015.